Phase 1 Trial of Bortezomib Plus R-CHOP in Previously Untreated Patients With Aggressive Non-Hodgkin Lymphoma

BACKGROUND: Bortezomib has preclinical and clinical in B-cell lymphomas, both alone and in combination with other agents. A phase 1 evaluation was conducted of bortezomib with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with untreated diffuse large B-cell lymphoma (DLBCL) or mantle cell lymphoma (MCL). METHODS: Twenty patients (16 with DLBCL and 4 with MCL) with a median age of 66 years (range, 29-84 years) were enrolled. Eleven subjects (55%) had an elevated lactate dehydrogenase level, and 10 patients (50%) had International Prognostic Index scores of 3 to 5. Standard R-CHOP was administered on a 21-day cycle for 6 cycles, with 1 of 3 dose levels of bortezomib (0.7 mg/m(2) [n = 4 patients], 1.0 mg/m(2) [n = 9 patients], or 1.3 mg/m(2) [n = 7 patients]) administered on Days 1 and 4 of each cycle. RESULTS: The maximum tolerated dose of bortezomib with R-CHOP was not reached, and the 1.3-mg/m(2) dose level had acceptable tolerability. A dose-limiting toxicity (pulmonary) was only observed in 1 patient receiving 1.0 mg/m(2) of bortezomib. Neuropathy occurred in 13 patients (65%), but was mostly grade 1 (45%) and reached grade 3 in only 1 patient (all toxicities were graded using the Common Terminology Criteria for Adverse Events, version 3.0). Grade 4 hematologic toxicity occurred in 7 patients (35%). Of 19 evaluable patients, all responded, with 18 (95%) cases of complete response/complete response unconfirmed achieved and 1 (5%) partial response reported. At a median follow-up of 56 months, overall survival at 4 years was 75% and progression-free survival was 58%. CONCLUSIONS: Bortezomib at a dose of 1.3 mg/m(2) twice per cycle can be added to R-CHOP chemotherapy with acceptable toxicity. Multi-institutional and cooperative group follow-up studies of this regimen are currently ongoing. Cancer 2010;116:5432-9. (C) 2010 American Cancer Society.